Peer-Reviewed Journal Details
Mandatory Fields
MCGAHON, AJ,NISHIOKA, WK,MARTIN, SJ,MAHBOUBI, A,COTTER, TG,GREEN, DR;
1995
September
The Journal of Biological Chemistry
REGULATION OF THE FAS APOPTOTIC CELL-DEATH PATHWAY BY ABL
Validated
()
Optional Fields
INTERLEUKIN-3 DEPENDENCE MOLECULAR-CLONING SURFACE ANTIGEN EXPRESSION MICE RAS ACTIVATION VIRUS LINE DIFFERENTIATION
270
22625
22631
Relatively little is known about oncogene involvement in the regulation of Fas-mediated apoptosis. Inhibition of Pas-induced cell death by the bcl-2 oncogene has been demonstrated to be only partial. In light of a growing body of evidence for the Abl kinase as a negative regulator of cell death, we sought to determine whether Abl expression could protect against Pas-mediated cell death. To address this question, we utilized two separate strategies. In the first, we expressed human Fas in K562, a chronic myelogenous leukemia cell line, which constitutively expresses bcr-abl and examined the effects of Fas ligation in these cells. Fas-positive K562 transformants (K562.Fas) were found to be protected against Pas-mediated cell death. However, down-regulation of Bcr-Abl protein levels in K562,Fas cells using antisense oligonucleotides targeted to bcr-abl mRNA rendered these cells highly susceptible to Fas-induced death. In the second approach we utilized a Fas-positive HL-60 cell line, which we transfected with a temperature-sensitive mutant of v-Abl. HL-60.v-AbI(ts) transfectants were found to be protected from Fas-induced apoptosis at the permissive but not the restrictive temperature for the Abl kinase. Taken together, these observations identify the Abl kinase as a negative regulator of Pas-mediated cell death. Since Abl was also found to block apoptosis mediated by ceramide, a recently proposed downstream effector of the apoptotic pathway initiated by Fas, we propose that Abl exerts its protective effects downstream of the early Fas-initiated signaling events.
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